The Innate Immune System and TRAIL-BCL-XL Axis Mediate a Sex Bias in Lung Cancer and Confer a Therapeutic Vulnerability in Females.

There is a significant sex-bias in lung cancer with males showing increased mortality compared to females. A better mechanistic understanding of these differences could help identify therapeutic targets to personalize cancer therapies to each sex. After observing a clear sex-bias in humanized mice, with male patient-derived xenograft (PDX) lung tumors being more progressive and deadlier than female PDX lung tumors, we identified mouse tumor models of lung cancer with the same sex-bias. This sex-bias was not observed in models of breast, colon, melanoma, and renal cancers. In vivo, the sex-bias in growth and lethality required intact ovaries, functional innate natural killer (NK) cells and monocytes/macrophages, and the activating receptor NKG2D. Ex vivo cell culture models were sensitized to the anti-cancer effects of NKG2D-mediated NK cell and macrophage killing through the TRAIL-BCL-XL axis when cultured with serum from female mice with intact ovaries. In both flank and orthotopic models, the BCL-XL inhibitor navitoclax (ABT-263) improved tumor growth control in female mice and required NK cells, macrophages, and the TRAIL signaling pathway. This research suggests that navitoclax and TRAIL pathway agonists could be used as a personalized therapy to improve outcomes in women with lung cancer.

α -KIDS: A novel feature evaluation in the ultrahigh-dimensional right-censored setting, with application to Head and Neck Cancer.

Recent advances in sequencing technologies have allowed collection of massive genome-wide information that substantially enhances the diagnosis and prognosis of head and neck cancer. Identifying predictive markers for survival time is crucial for devising prognostic systems, and learning the underlying molecular driver of the cancer course. In this paper, we introduce α -KIDS, a model-free feature screening procedure with false discovery rate (FDR) control for ultrahigh dimensional right-censored data, which is robust against unknown censoring mechanisms. Specifically, our two-stage procedure initially selects a set of important features with a dual screening mechanism using nonparametric reproducing-kernel-based ANOVA statistics, followed by identifying a refined set (of features) under directional FDR control through a unified knockoff procedure. The finite sample properties of our method, and its novelty (in light of existing alternatives) are evaluated via simulation studies. Furthermore, we illustrate our methodology via application to a motivating right-censored head and neck (HN) cancer survival data derived from The Cancer Genome Atlas, with further validation on a similar HN cancer data from the Gene Expression Omnibus database. The methodology can be implemented via the R package DSFDRC, available in GitHub.

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma.

Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors.

The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.

Lung Cancer Prevalence in Virginia: A Spatial Zipcode-Level Analysis via INLA.

BACKGROUND: Examining lung cancer (LC) cases in Virginia (VA) is essential due to its significant public health implications. By studying demographic, environmental, and socioeconomic variables, this paper aims to provide insights into the underlying drivers of LC prevalence in the state adjusted for spatial associations at the zipcode level. METHODS: We model the available VA zipcode-level LC counts via (spatial) Poisson and negative binomial regression models, taking into account missing covariate data, zipcode-level spatial association and allow for overdispersion. Under latent Gaussian Markov Random Field (GMRF) assumptions, our Bayesian hierarchical model powered by Integrated Nested Laplace Approximation (INLA) considers simultaneous (spatial) imputation of all missing covariates through elegant prediction. The spatial random effect across zip codes follows a Conditional Autoregressive (CAR) prior. RESULTS: Zip codes with elevated smoking indices demonstrated a corresponding increase in LC counts, underscoring the well-established connection between smoking and LC. Additionally, we observed a notable correlation between higher Social Deprivation Index (SDI) scores and increased LC counts, aligning with the prevalent pattern of heightened LC prevalence in regions characterized by lower income and education levels. On the demographic level, our findings indicated higher LC counts in zip codes with larger White and Black populations (with Whites having higher prevalence than Blacks), lower counts in zip codes with higher Hispanic populations (compared to non-Hispanics), and higher prevalence among women compared to men. Furthermore, zip codes with a larger population of elderly people (age ≥ 65 years) exhibited higher LC prevalence, consistent with established national patterns. CONCLUSIONS: This comprehensive analysis contributes to our understanding of the complex interplay of demographic and socioeconomic factors influencing LC disparities in VA at the zip code level, providing valuable information for targeted public health interventions and resource allocation. Implementation code is available at GitHub.

Partly linear single-index cure models with a nonparametric incidence link function.

In cancer studies, it is commonplace that a fraction of patients participating in the study are cured, such that not all of them will experience a recurrence, or death due to cancer. Also, it is plausible that some covariates, such as the treatment assigned to the patients or demographic characteristics, could affect both the patients' survival rates and cure/incidence rates. A common approach to accommodate these features in survival analysis is to consider a mixture cure survival model with the incidence rate modeled by a logistic regression model and latency part modeled by the Cox proportional hazards model. These modeling assumptions, though typical, restrict the structure of covariate effects on both the incidence and latency components. As a plausible recourse to attain flexibility, we study a class of semiparametric mixture cure models in this article, which incorporates two single-index functions for modeling the two regression components. A hybrid nonparametric maximum likelihood estimation method is proposed, where the cumulative baseline hazard function for uncured subjects is estimated nonparametrically, and the two single-index functions are estimated via Bernstein polynomials. Parameter estimation is carried out via a curated expectation-maximization algorithm. We also conducted a large-scale simulation study to assess the finite-sample performance of the estimator. The proposed methodology is illustrated via application to two cancer datasets.

CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma.

Tumor budding (TB) is a small tumor cell cluster with highly aggressive behavior located ahead of the invasive tumor front. However, the molecular and biological characteristics of TB and the regulatory mechanisms governing TB phenotypes remain unclear. This study reveals that TB exhibits a particular dynamic gene signature with stemness and partial epithelial-mesenchymal transition (p-EMT). Importantly, nuclear expression of CYTOR is identified to be the key regulator governing stemness and the p-EMT phenotype of TB cells, and targeting CYTOR significantly inhibits TB formation, tumor growth and lymph node metastasis in head and neck squamous cell carcinoma (HNSCC). Mechanistically, CYTOR promotes tumorigenicity and metastasis of TB cells by facilitating the formation of FOSL1 phase-separated condensates to establish FOSL1-dependent super enhancers (SEs). Depletion of CYTOR leads to the disruption of FOSL1-dependent SEs, which results in the inactivation of cancer stemness and pro-metastatic genes. In turn, activation of FOSL1 promotes the transcription of CYTOR. These findings indicate that CYTOR is a super-lncRNA that controls the stemness and metastasis of TB cells through facilitating the formation of FOSL1 phase separation and SEs, which may be an attractive target for therapeutic interventions in HNSCC.

Concordant care in sentinel lymph node omission following Choosing Wisely® recommendations at a comprehensive cancer center.

BACKGROUND: In 2016, the SSO and ABIM released a Choosing Wisely® guideline stating SLNB can be safely omitted in women ≥70 with HR â€‹+ â€‹HER-invasive breast cancer. No study evaluating concordance of care with this guideline has been performed within a comprehensive cancer center. METHODS: From 2005 to 2020, there were 382 patients with cT1-2N0 invasive carcinoma ER+/PR+ and HER2-identified as having undergone SLNB. These patients were then separated into two groups; those in the pre-guideline concordance cohort (2005-2015) and those in the post-guideline concordance (2016-2020) cohort. Axillary management concordance was trended over time. RESULTS: 382 patients from 2005 to 2020 with HR â€‹+ â€‹HER- IBC were identified. No difference was seen in SLNB pre-versus post-guidelines (p â€‹= â€‹0.35). Increased concordance was noted as age increased (p â€‹= â€‹0.0068) and adjuvant radiation therapy exclusion (p â€‹< â€‹0.0001) post-guideline release. Concordance improved over the years post-guideline release (R2 â€‹= â€‹0.45). CONCLUSIONS: Surgical guideline adoption occurs over time but may also be affected by outside decisions and factors. Further study into patterns of guideline adoption may facilitate improving adherence to guidelines.

Luminal A Versus B After Choosing Wisely: Does Lymph Node Surgery Affect Oncologic Outcomes?

BACKGROUND: In 2016, the Choosing Wisely campaign recommended against routine sentinel lymph node biopsy (SLNB) in women ≥ 70 years old diagnosed with early-stage hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer. No distinction is made between luminal A and luminal B phenotypes, despite luminal B being considered more aggressive. This study evaluates the effect of SLNB on oncologic outcomes in HER2- luminal B versus luminal A breast cancer. PATIENTS AND METHODS: We performed an IRB-approved, single institution, retrospective cohort study from 2010 to 2020 of women aged ≥ 70 years with clinically node negative, HR+ breast cancer undergoing definitive surgical treatment. Luminal status was defined by gene expression panel testing, Ki67%, and/or pathologic grading. Primary endpoints included locoregional recurrence (LRR), disease free survival (DFS), and overall survival (OS). RESULTS: SLNB did not correlate with significant differences in LRR in luminal A (p = 0.92) or luminal B (p = 0.96) disease. SLNB correlated with improved DFS (p < 0.01) and OS (p < 0.001) in luminal A disease, but not in luminal B disease (DFS p = 0.73; OS p = 0.36). On multivariate analysis, age (HR = 1.17; p < 0.01) and tumor size (HR = 1.03; p < 0.05) were associated with DFS, while SLNB was not (p = 0.71). Luminal status (HR = 0.52, p < 0.05), age (HR = 1.15, p < 0.01), and comorbidities (HR = 1.35, p < 0.05) were associated with OS, but not SLNB (p = 0.71). CONCLUSIONS: Our results suggest that SLNB may be safely omitted in patients aged ≥ 70 years with luminal B disease given similar LRR in luminal A disease. Our findings suggest that DFS and OS are driven by tumor biology, patient age, and comorbidities rather than receipt of SLNB.

Higher diet quality relates to better cardiac function in cancer survivors: The multi-ethnic study of atherosclerosis.

BACKGROUND: Cancer therapies induce cardiac injury and increase cardiovascular disease (CVD) risk. In non-cancer populations, higher diet quality is associated with protection against CVD, but the relationship between diet and cardiac function in cancer survivors is unknown. METHODS: This cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort included 113 cancer survivors (55 breast, 53 prostate, three lung, and three blood) and 4233 non-cancer controls. Dietary intake was reported via validated food frequency questionnaire. Alternate healthy eating index (AHEI) was calculated as a measure of quality. Cardiac function, determined as left ventricular ejection fraction (LVEF), was assessed by cardiac magnetic resonance. RESULTS: Cancer survivors had a lower LVEF compared to controls (61.3 ± 6.5% v 62.4 ± 6.1%, p = 0.04). In all participants, total fat (ß ± SE: -0.04 ± 0.01, p = 0.004), saturated fat (-0.11 ± 0.03, p < 0.001), and trans-fat (-0.36 ± 0.12, p = 0.002) intake were inversely associated with LVEF while AHEI (0.03 ± 0.01, p < 0.001) was positively associated with LVEF. Among cancer survivors only, sucrose intake was negatively related to LVEF (-0.15 ± 0.06, p = 0.02), and the ratio of unsaturated fat to saturated fat (2.7 ± 1.1, p = 0.01) and fiber intake (0.42 ± 0.14, p = 0.003) were positively related to LVEF. DISCUSSION: In cancer survivors, improved dietary fat and carbohydrate quality (i.e., greater consumption of unsaturated fatty acids and fiber) was associated with favorable cardiac function, while higher sucrose was associated with worse cardiac function. Further research is needed to confirm these findings and test whether changes in the identified dietary factors will modulate cardiac function in cancer survivors.

Racial/Ethnic Disparities in the Era of Minimally Invasive Surgery for Treatment of Colorectal Cancer.

BACKGROUND: Minimally invasive (laparoscopic and robotic) surgery (MIS) for colorectal cancer is associated with improved outcomes. We sought to characterize possible disparities in surgical approach and outcomes. PATIENTS AND METHODS: In this cross-sectional study, colorectal adenocarcinoma cases among non-Hispanic white (NHW), non-Hispanic Black (NHB), and Hispanic patients were identified using the National Cancer Database (2010-2017). Logistic and Poisson regressions, generalized logit models, and Cox proportional hazards were used to assess outcomes, with reclassification of surgery type if converted to open. RESULTS: NHB patients were less likely to undergo robotic surgery. After multivariable analysis, NHB patients were 6% less likely, while Hispanic patients were 12% more likely to undergo a MIS approach. Lymph node retrieval was higher (> 1.3% more, p < 0.0001) and length of stay was shorter (> 17% shorter, p < 0.0001) for MIS approaches. Unplanned readmission was lower for MIS colon cancer operations compared with open operations, but not for rectal cancer. Race/ethnicity-adjusted risk of death was lower with MIS approaches for colon as well as rectal cancer. After adjusting for surgery type, risk of death was 12% lower for NHB and 35% lower for Hispanic patients compared with NHW patients. Hispanic patients had 21% lower risk of death, while NHB patients had 12% higher risk of death than NHW patients with rectal cancer, after adjusting for surgery type. CONCLUSIONS: Racial/ethnic disparities exist in utilization of MIS for colorectal cancer treatment, disproportionately affecting NHB patients. Since MIS has the potential to improve outcomes, suboptimal access may contribute to harmful and thus unacceptable disparities in survivorship.

Malignant choroidal melanoma with vitreous seeds: supported by histopathology and field emission scanning electron microscopy study.

Aim: To report an exceptionally rare case of malignant choroidal melanoma with vitreous seeding, supported by histopathological and field emission scanning electron microscopic (FESEM) studies. Case report: A 58-year-old male with painless diminution of vision in his left eye for past 1 month was found to have a brown retrolental mass lesion on slit lamp examination in the left eye. Detailed fundus examination revealed choroidal melanoma in the left eye with pigmented seeds extending into the vitreous cavity and associated exudative retinal detachment. Ocular imaging was consistent with the diagnosis. Results: The eyeball was enucleated and the tumor was considered as stage IIB (AJCC 8th edition classification). Metastatic workup of the patient was negative. One half of the eyeball was subjected to field emission scanning electron microscopy to further study the nature and appearance of vitreous seeds. Discussion: Vitreous seeding in choroidal melanoma has been reported only in a handful of cases in literature. Histopathological confirmation of vitreous seeds was done in our case and morphological detailing was performed using FESEM study. Conclusions: Treatment naïve choroidal melanoma can very rarely have vitreous seeds. Early enucleation in such cases carries a favorable prognosis.

Myocardial Strain during Surveillance Screening Is Associated with Future Cardiac Dysfunction among Survivors of Childhood, Adolescent and Young Adult-Onset Cancer.

Cardiovascular disease is a leading contributor to mortality among childhood, adolescent and young adult (C-AYA) cancer survivors. While serial cardiovascular screening is recommended in this population, optimal screening strategies, including the use of echocardiography-based myocardial strain, are not fully defined. Our objective was to determine the relationship between longitudinal and circumferential strain (LS, CS) and fractional shortening (FS) among survivors. This single-center cohort study retrospectively measured LS and CS among C-AYAs treated with anthracycline/anthracenedione chemotherapy. The trajectory of LS and CS values over time were examined among two groups of survivors: those who experienced a reduction of >5 fractional shortening (FS) units from pre-treatment to the most recent echocardiogram, and those who did not. Using mixed modeling, LS and CS were used to estimate FS longitudinally. A receiver operator characteristic curve was generated to determine the ability of our model to correctly predict an FS ≤ 27%. A total of 189 survivors with a median age of 14 years at diagnosis were included. Among the two survivor groups, the trajectory of LS and CS differed approximately five years from cancer diagnosis. A statistically significant inverse relationship was demonstrated between FS and LS -0.129, p = 0.039, as well as FS and CS -0.413, p < 0.001. The area under the curve for an FS ≤ 27% was 91%. Among C-AYAs, myocardial strain measurements may improve the identification of individuals with cardiotoxicity, thereby allowing earlier intervention.

Outcomes of Cancer Patients with COVID-19: The Virginia Commonwealth University Experience.

PURPOSE: The cancer population is significantly impacted by coronavirus disease 2019 (COVID-19) due to inherent risks of infection imposed by malignancy and therapeutic agents. Evaluating risk factors in this group will lead to improved guidelines for the treatment of malignancy in the setting of a COVID-19 pandemic. PATIENTS AND METHODS: This retrospective study reviewed 295 inpatient cancer patients positive for COVID-19 between February 2020 and December 2021 to determine specific risk factors of mortality and associated complications. Various patient characteristics were collected to evaluate outcomes in patient death, oxygen requirement, ventilatory support, and increased length of stay. RESULTS: 31 (10.5%) of 295 patients died due to COVID-19. Of those that died, the majority had hematologic cancer (48.4%). There was no difference in the odds of death among the cancer groups. Those vaccinated had a reduced risk of death (OR 0.04, CI 0-0.23). Patients with lung cancer (OR 3.69, CI 1.13-12.31), obesity (OR 3.27, CI 1.18-9.27), CHF (OR 2.68, CI 1.07-6.89) were more likely to require ventilation. Those treated with hormonal therapy had higher odds of having a prolonged admission (OR 5.04, CI 1.17-2.53). Otherwise, cancer therapy had no significant difference in any outcome. CONCLUSION: The mortality rate of cancer patients was 10.5%, lower than in other studies. Vaccinations had mortality benefits, but no effect on hypoxia, ventilator use, or LOS. Delaying cancer therapy during peak infection is likely not necessary based on the results of this study. With improved knowledge in the risks of infection and the utility of personalized precautions, both providers and patients can better prepare for another potential wave of COVID-19.

Using Oncotype DX breast recurrence score® assay to define the role of neoadjuvant endocrine therapy in early-stage hormone receptor-positive breast cancer.

PURPOSE: The role of neoadjuvant endocrine therapy in the treatment of patients with early-stage, hormone receptor-positive (HR +) breast cancer is not well defined. Tools to better determine which patients may benefit from neoadjuvant endocrine therapy versus chemotherapy or upfront surgery remain an unmet need. METHODS: We assessed the rate of clinical and pathologic complete response (cCR, pCR) among a pooled cohort of patients with early-stage HR + breast cancer who had been randomized to neoadjuvant endocrine therapy or neoadjuvant chemotherapy in two earlier studies to understand better how outcomes varied by Oncotype DX Breast Recurrence Score® assay. RESULTS: We observed that patients with intermediate RS results had no statistically significant differences in pathologic outcomes at the time of surgery based on whether they received neoadjuvant endocrine therapy or neoadjuvant chemotherapy, suggesting that a subgroup of women with a RS 0-25 may omit chemotherapy without compromising outcomes. CONCLUSION: These data suggest that Recurrence Score® (RS) results may serve as a useful tool in treatment decision-making in the neoadjuvant setting.

Phase 1 study of belinostat and adavosertib in patients with relapsed or refractory myeloid malignancies.

PURPOSE: Belinostat is an intravenous histone deacetylase inhibitor with approval for T-cell lymphomas. Adavosertib is a first in class oral Wee1 inhibitor. Preclinical studies of the combination demonstrated synergy in various human acute myeloid leukemia (AML) lines as well as AML xenograft mouse models. EXPERIMENTAL DESIGN: This was a phase 1 dose-escalation study of belinostat and adavosertib in patients with relapsed/refractory AML and myelodysplastic syndrome (MDS). Patients received both drugs on days 1-5 and 8-12 of a 21-day cycle. Safety and toxicity were monitored throughout the study. Plasma levels of both drugs were measured for pharmacokinetic analysis. Response was determined by standard criteria including bone marrow biopsy. RESULTS: Twenty patients were enrolled and treated at 4 dose levels. A grade 4 cytokine release syndrome at dose level 4 (adavosertib 225 mg/day; belinostat 1000 mg/m2) qualified as a dose-limiting toxicity event. The most common non-hematologic treatment-related adverse events were nausea, vomiting, diarrhea, dysgeusia, and fatigue. No responses were seen. The study was terminated prior to maximum tolerated dose/recommended phase 2 dose determination. CONCLUSIONS: The combination of belinostat and adavosertib at the tested dose levels was feasible but without efficacy signals in the relapsed/refractory MDS/AML population.

Racial disparities in opioid prescription and pain management among breast cancer survivors.

BACKGROUND: We examined whether there are racial disparities in pain management, opioid medicine prescriptions, symptom severity, and quality of life constructs in breast cancer survivors. METHODS: We conducted a secondary analysis of longitudinal data from the Women's Hormonal Therapy Initiation and Persistence (WHIP) study (n = 595), a longitudinal study of hormonal receptor-positive breast cancer survivors. Upon study enrollment, patients completed a survey assessing an array of psychological, behavioral, and treatment outcomes, including adjuvant endocrine therapy (AET)-induced symptoms, and provided a saliva biospecimen. Opioid prescription records were extracted from the health maintenance organizations (HMOs) pharmacy database. The final analytic sample included women with complete HMO pharmacy records for 1 year. RESULTS: There were 251 eligible patients, of which 169 (67.3%) were White. The average age was 61.09 years old (SD = 11.07). One hundred seventy-two patients (68.5%) had received at least one opioid medication and 37.1% were prescribed opioids longer than 90 days (n = 93). Sixty-four Black patients (78%) had a record of being prescribed with opioids compared to 64% of White patients (n = 108, p = 0.03). Black patients reported worse vasomotor, neuropsychological, and gastrointestinal symptoms, as well as lower quality of life and greater healthcare discrimination than White patients (p's < 0.05). Black patients were more likely to be prescribed opioids for 90 days or longer compared to White patients, when controlling for age, marital status, income, body mass index (BMI), cancer stage, and chemotherapy status (adjusted Odds Ratio = 2.72, p = 0.014). CONCLUSION: Findings indicate that there are racial differences in opioid prescriptions supplied for pain management and symptomatic outcomes. Future research is needed to understand the causes of disparities in cancer pain management and symptomatic outcomes.

Change in vaginal length and sexual function in women who undergo surgery ± radiation therapy for endometrial cancer.

PURPOSE: Endometrial Cancer (EC) is the most common gynecologic malignancy in the United States. Standard treatment is TAH/BSO with radiation therapy (RT) and chemotherapy given based on risk. Treatment can cause significant vaginal changes, including shortening, narrowing, loss of elasticity, atrophy, and dryness. These are not life threatening, but affect a woman's physical, psychological, and social functioning. Adjuvant vaginal dilator use is often advised, but there are inconsistent recommendations on use. This prospective study compared vaginal length changes and sexual function in women compliant with dilation versus not after surgery and RT. METHODS AND MATERIALS: Enrolled patients underwent surgery for Stage I-IIIC EC ±RT. Vaginal dilator use was recommended for women receiving RT (external beam or brachytherapy). Vaginal length was measured with a vaginal sound and the Female Sexual Function Index (FSFI) was used to assess sexual function. RESULTS: Forty-one enrolled patients had sufficient data for analysis. Dilation significantly increased FSFI scores (p = 0.02) while RT without dilation showed a significant decrease (p = 0.04). Dilation helped maintain vaginal length for all patients (0 cm vs. 1.8 cm loss (p = 0.03)). Individual arms did not show statistically significant changes in length with dilation, though the trend showed RT without dilation had an average loss of 2.3 cm as compared to only 0.2 cm for regular dilation. Notably, there was no difference in length change with dilation for surgery alone versus surgery and RT (p = 0.14). CONCLUSION: This data provides novel, prospective evidence of the benefit of vaginal dilation for maintaining vaginal length and improving sexual health after any pelvic treatment for EC. This evidence also supports that the addition of RT after surgery does not appear to significantly worsen vaginal shortening. This study has important implications for providing a strong foundation for future studies and helping to establish solid clinical management criteria for the prevention of vaginal stenosis and promotion of female sexual health.

Gene Screening for Prognosis of Non-Muscle-Invasive Bladder Carcinoma under Competing Risks Endpoints.

Background: Discovering clinically useful molecular markers for predicting the survival of patients diagnosed with non−muscle-invasive bladder cancer can provide insights into cancer dynamics and improve treatment outcomes. However, the presence of competing risks (CR) endpoints complicates the estimation and inferential framework. There is also a lack of statistical analysis tools and software for coping with the high-throughput nature of these data, in terms of marker screening and selection. Aims: To propose a gene screening procedure for proportional subdistribution hazards regression under a CR framework, and illustrate its application in using molecular profiling to predict survival for non-muscle invasive bladder carcinoma. Methods: Tumors from 300 patients diagnosed with bladder cancer were analyzed for genomic abnormalities while controlling for clinically important covariates. Genes with expression patterns that were associated with survival were identified through a screening procedure based on proportional subdistribution hazards regression. A molecular predictor of risk was constructed and examined for prediction accuracy. Results: A six-gene signature was found to be a significant predictor associated with survival of non−muscle-invasive bladder cancer, subject to competing risks after adjusting for age, gender, reevaluated WHO grade, stage and BCG/MMC treatment (p-value < 0.001). Conclusion: The proposed gene screening procedure can be used to discover molecular determinants of survival for non−muscle-invasive bladder cancer and in general facilitate high-throughput competing risks data analysis with easy implementation.